Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 24, Issue 8, Pages 1416-1421Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000134299.89599.53
Keywords
Tenascin-C; metalloproteinases; atherosclerosis; apoptosis; EGF-like domain
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Funding
- NHLBI NIH HHS [R01 HL090653, R01 HL104068, HL50566] Funding Source: Medline
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Objective-Based on our previous observations on the expression of Tenascin-C (Tn-C) in human atherosclerotic plaques and its colocalization with macrophages, we explored whether Tn-C undergoes fragmentation and the potential pathobiological significance of this fragmentation. Methods and Results-Using cultured human smooth muscle cells (SMCs), we found that Tn-C upregulates expression of matrix metalloproteinases (MMPs). Western blot analysis revealed that Tn-C substrate is fragmented and most of the cleavage products have fibronectin-like and epidermal growth factor-like (EGF-like) domains of Tn-C. One fragment that contains an EGF-like domain was found in some human atherosclerotic plaques. Cell culture studies revealed that the recombinant EGF-like domain inhibits growth, induces apoptosis of SMCs in a dose-dependent, time-dependent, and caspase-dependent manner, and activates caspase-3 before SMC detachment. Conversely, the caspase inhibitor z-YVAD. cmk, serum, and protease inhibitors blocked cell apoptosis conferred by the EGF-like domain. In addition, these inhibitors blocked EGF-like domain-induced caspase-3 activation. In contrast to this EGF-like domain, intact Tn-C, its fibronectin-like, and its fibrinogen-like domains were inactive. Conclusions-Together with our previous observations, our data suggest that Tn-C upregulates MMP expression that cleaves Tn-C into fragments containing the EGF-like domain. This domain has proapoptotic activity for SMCs.
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